Preparation of 2,7-diazabicyclo[3.3.0]octanes

ABSTRACT

2,7-Diazabicyclo[3.3.0]octanes, suitable for 7-position substituents or antibacterially active quinolone carboxylic acids, of the formula ##STR1## in which R 1 , R 3 , R 4 , R 5 , R 7  and R 8  may be identical or different and in each case denote H, C 1  -C 5  -alkyl (optionally substituted by halogen, hydroxyl or C 1  -C 3  -alkoxy), C 1  -C 3  -alkoxycarbonyl or C 6  -C 12  -aryl, 
     R 4  additionally denotes halogen, 
     R 2  and R 6  may be identical or different, denote H, C 1  -C 6  -alkyl, benzyl, C 6  -C 12  -aryl, C 1  -C 3  -alkanoyl, benzoyl or C 1  -C 5  -alkoxycarbonyl, or 
     R 2  and R 3  together denote a bridge of the structure (CH 2 ) n , n=2-4, CH 2  --CHOH--CH 2 , CH 2  --S--CH 2  or C(CH 3 ) 2  --S--CH 2 , 
     excluding 2,7-diazabicyclo[3.3.0]octane. 
     Also their preparation by the reaction ##STR2## Intermediates II are also new.

The present invention relates to 2,7-diazabicyclo [3.3.0]octanes and toa process for their preparation. The compounds according to theinvention are useful intermediates for the preparation of highly activeantibacterial quinolonecarboxylic acids.

It has already been disclosed that 2,7-diazabicyclo [3.3.0]octane(octahydropyrrolo[3,4-b]pyrrole)can be prepared by reduction withlithium aluminum hydride from 2,7-diazabicyclo[3.3.0]octane-3,8-dione.This compound was prepared by addition of diazomethane to dimethylglutaconate and subsequent cleavage by hydrogenation of the intermediatepyrazoline derivative (Justus Liebigs Ann. Chemie 677, 154 (1964)). Thisprocess involves the disadvantage of contact with the highly toxic andexplosive diazomethane and is of no use for industrial applicationMoreover, substituted glutaconic acid esters can only be prepared withdifficulty, so that this process is not easily capable of generalapplication.

The invention relates to 2,7-diazabicyclo[3.3.0]-octanes of the formula(I) ##STR3## where R¹, R³, R⁴, R⁵, R⁷ and R⁸ may be identical ordifferent, in each case denote H, C₁₋ C₅ -alkyl, optionally substitutedby halogen, hydroxyl or C₁₋ C₄ -alkoxy, C₁₋ C₃ -alkoxycarbonyl or C₆₋C₁₂ -aryl, preferably H, C₁₋ C₃ -alkyl, C₁₋ C₃ -alkoxycarbonyl orphenyl, particularly preferably H or methyl,

R⁴ additionally denotes halogen, preferably fluorine, chlorine orbromine, particularly preferably chlorine or bromine,

R² and R⁶ may be identical or different and denote H, C₁₋ C₆ -alkyl,benzyl, C₆₋ C₁₂ -aryl, C₁₋ C₃ -alkanoyl, benzoyl or C₁₋ C₅-alkoxycarbonyl, preferably H, C₁₋ C₃ -alkyl, benzyl, C₆₋ C₁₂ -aryl, C₁₋C₂ -alkanoyl, benzoyl or C₁₋ C₄ -alkoxycarbonyl, particularly preferablyH, methyl, phenyl, acetyl or C₂₋ C₄ -alkoxycarbonyl and

R² and R³ together optionally denote a bridge of the structure(CH₂)_(n), n=2-4, CH₂₋₋ CHOH--CH₂, CH₂₋₋ S--CH₂ or C(CH₃)₂₋₋ S--CH₂,

excluding 2,7-diazabicyclo[3.3.0]octane.

Particularly preferred compounds are those of the following formuale:##STR4##

The C₆₋ C₁₂ -aryl radical can be substituted or unsubstituted. Possiblesubstituents are 1 to 3, preferably 1 substituent(s), from the groupcomprising halogen, in particular Cl, Br or F, amino, C₁₋ C₃-alkylamino, C₁₋ C₃ -dialkylamino, hydroxyl, C₁₋ C₃ -alkoxy, C₁₋ C₃-alkyl or cyano.

It has furthermore been found that 2,7-diazabicyclo [3.3.0]octanes ofthe formula (I) ##STR5## where R¹, R³, R⁴, R⁵, R⁷ and R⁸ may beidentical or different and in each case denote H, C₁₋ C₅ -alkyl,optionally substituted by halogen, hydroxyl or C₁₋ C₃ -alkoxy, C₁₋ C₃-alkoxycarbonyl or C₆₋ C₁₂ -aryl, preferably H, C₁₋ C₃ -alkyl, C₁₋ C₃-alkoxycarbonyl or phenyl, particularly preferably H and methyl,

R⁴ additionally denotes halogen, preferably fluorine, chlorine orbromine, particularly preferably chlorine or bromine,

R² and R⁶ may be identical or different and denote H, C₁₋ C₆ -alkyl,benzyl, C₆₋ C₁₂ -aryl, C₁₋ C₃ -alkanoyl, benzoyl or C₁₋ C₅-alkoxycarbonyl, preferably H, C₁₋ C₃ -alkyl, benzyl, C₆₋ C₁₂ -aryl, C₁₋C₂ -alkanoyl, benzoyl or C₁₋ C₄ -alkoxycarbonyl, particularly preferablyH, methyl, phenyl, acetyl or C₂₋ C₄ -alkoxycarbonyl and

R² and R³ together optionally denote a bridge of the structure(CH₂)_(n), n=2-4, CH₂₋₋ CHOH--CH₂, CH₂₋₋ S--CH₂ or C(CH₃)₂₋₋ S--CH₂,

are obtained by a process in which unsaturated carbonyl compounds of theformula (II) are reacted with amino acid derivatives of the formula(III) in an intramolecular 1,3-dipolar cycloaddition, ##STR6## in whichR' represents H or C₁₋ C₃ -alkyl and where R¹⁻ R⁶ have theabovementioned meanings The substituents R² or R⁶, which have aprotective group function, can then be removed.

The advantage of the process according to the invention consists in thesimplicity of carrying it out and in the easy availability of thestarting compounds (II) and (III). The high stereoselectivity of theprocess must be designated as particularly advantageous. This isparticularly surprising since similar cyclizations can lead to productmixtures (J. Chem. Soc., Chem. Comm. 1984, 182). Owing to theselectivity of the process claimed here, a high-loss and uneconomicalseparation of undesired diastereomers is unnecessary.

The course of the reaction of the process according to the invention maybe illustrated by the following examples: ##STR7##

The unsaturated carbonyl compounds of the formula (II) needed asstarting compounds are new. They can be prepared by the followingmethods:

1. Starting from commercially available aminoacetaldehyde dimethylacetal, the amino group is acylated, the amide is alkylated with allylhalides in the presence of strong bases and the acetal is cleaved underacidic conditions. ##STR8## The known acetamidoacetone dimethyl acetal(Synthesis 1988, 381) can be alkylated with allyl halides in thepresence of strong bases and the acetal group hydrolyzed under acidicconditions. ##STR9##

Starting from commercially available or known (EP 249,530, June 3, 1986)α-ketoaldehyde monoacetals, these can be reductively aminated withallylamines. After introducing a (protective) group R⁶ by alkylating oracylating, the acetal group is hydrolyzed under acidic conditions.##STR10##

Unsaturated aldehydes or ketones can be reductively aminated withaminoacetaldehyde dimethyl acetal. After introducing the group R⁶ byalkylating or acylating, the acetal group can be cleaved under acidicconditions. ##STR11##

N-Allylamino alcohols are obtained

a) by ring opening of epoxides with allylamindes (J. Pharm. Soc. Japan73, 1330 (1953)),

b) by alkylating substituted ethanolamines with allyl halides (J. Am.Chem. Soc. 64, 1692 (1942); 72, 3536 ((1950)),

c) by reductive amination of unsaturated aldehydes or ketones withsubstituted ethanolamines.

After introducing the group R⁶ by alkylating or acylating, the alcoholfunction is oxidized with suitable oxidizing agents to give compounds ofthe formula (II). ##STR12##

Enantiomerically pure precursors of the formula (II) are obtained byalkylating N-acylated amino acid esters with allyl halides in thepresence of strong bases. Using suitable reducing agents, the esterfunction can be

a) reduced to the aldehyde function or

b) reduced to the alcohol and then oxidized to the aldehyde functionusing suitable oxidizing agents. ##STR13##

Examples of precursors of the formula (II) which may be mentioned are:

methyl N-allyl-N-(2-oxoethyl)-carbamate,

ethyl N-allyl-N-(2-oxoethyl)-carbamate,

isopropyl N-allyl-N-(2-oxoethyl)-carbamate,

tert.-butyl N-allyl-N-(2-oxoethyl)-carbamate,

N-allyl-N-(2-oxoethyl)-acetamide,

N-allyl-N-(2-oxoethyl)-propionamide,

N-allyl-N-(2-oxoethyl)-benzamide,

methyl N-allyl-N-(1-oxoprop-2-yl)-carbamate,

ethyl N-allyl-N-(1-oxoprop-2-yl)-carbamate,

propyl N-allyl-N-(1-oxoprop-2-yl)-carbamate,

N-allyl-N-(1-oxoprop-2-yl)-acetamide,

N-allyl-N-(1-oxoprop-2-yl)-benzamide,

methyl N-(buten-3-yl)-N-(2-oxoethyl)-carbamate,

ethyl N-(buten-3-yl)-N-(2-oxoethyl)-carbamate,

1isopropyl N-(buten-3-yl)-N-(2-oxoethyl)-carbamate,

tert.-butyl N-(buten-3-yl)-N-(2-oxoethyl)-carbamate,

N-(buten-3-yl)-N-(2-oxoethyl)-acetamide,

N-(buten-3-yl)-N-(2-oxoethyl)-benzamide,

methyl N-(2-methylallyl)-N-(2-oxoethyl)-carbamate,

ethyl N-(2-methylallyl)-N-(2-oxoethyl)-carbamate,

N-(2-methylallyl)-N-(2-oxoethyl)-acetamide,

N-(2-methylallyl)-N-(2-oxoethyl)-benzamide,

methyl N-(2-fluoroallyl)-N-(2-oxoethyl)-carbamate,

ethyl N-(2-fluoroallyl)-N-(2-oxoethyl)-carbamate,

N-(2-fluoroallyl)-N-(2-oxoethyl)-acetamide,

N-(2-fluoroallyl)-N-(2-oxoethyl)-benzamide,

methyl N-(2-chloroallyl)-N-(2-oxoethyl)-carbamate,

ethyl N-(2-chloroallyl)-N-(2-oxoethyl)-carbamate,

N-(2-chloroallyl)-N-(2-oxoethyl)-acetamide,

N-(2-chloroallyl)-N-(2-oxoethyl)-benzamide,

methyl N-(2-bromoallyl)-N-(2-oxoethyl)-carbamate,

ethyl N-(2-bromoallyl)-N-(2-oxoethyl)-carbamate,

N-(2-bromoallyl)-N-(2-oxoethyl)-acetamide,

N-(2-bromoallyl)-N-(2-oxoethyl)-benzamide,

methyl N-(2-ethoxycarbonylallyl)-N-(2-oxoethyl) -carbamate,

ethyl N-(2-ethoxycarbonylallyl)-N-(2-oxoethyl)-carbamate,

N-(2-ethoxycarbonylallyl)-N-(2-oxoethyl)-acetamide,

N-(2-ethoxycarbonylallyl)-N-(2-oxoethyl)-benzamide,

ethyl N-(2-oxoethyl)-N-(2-phenylallyl)-carbamate,

methyl N-(2-buten-1-yl)-N-(2-oxoethyl)-carbamate,

ethyl N-(2-buten-1-yl)-N-(2-oxoethyl)-carbamate,

N-(2-buten-1-yl)-N-(2-oxoethyl)-acetamide,

N-(2-buten-1-yl)-N-(2-oxoethyl)-benzamide,

methyl N-(3-chloroallyl)-N-(2-oxoethyl)-carbamate,

ethyl N-(3-chloroallyl)-N-(2-oxoethyl)-carbamate,

N-(3-chloroallyl)-N-(2-oxoethyl)-acetamide,

N-(3-chloroallyl)-N-(2-oxoethyl)-benzamide,

methyl N-(3-phenylallyl)-N-(2-oxoethyl)-carbamate,

ethyl N-(3-phenylallyl)-N-(2-oxoethyl)-carbamate,

N-(3-phenylallyl)-N-(2-oxoethyl)-acetamide,

N-(3-phenylallyl)-N-(2-oxoethyl)-benzamide,

methyl N-(3-ethoxycarbonylallyl)-N-(2-oxoethyl) -carbamate,

ethyl N-(3-ethoxycarbonylallyl)-N-(2-oxoethyl)-carbamate,

N-(3-ethoxycarbonylallyl)-N-(2-oxoethyl)-acetamide,

ethyl N-allyl-N-(2-oxopropyl)-carbamate,

N-allyl-N-(2-oxopropyl)-acetamide,

N-allyl-N-(2-oxopropyl)-benzamide,

N-allyl-N-(2-oxo-2-phenylethyl)-acetamide,

N-allyl-N-(2-ethoxycarbonyl-2-oxoethyl)-acetamide,

N-allyl-N-benzyl-N-2-(oxopropyl)-amine,

N-benzyl-N-(2-methylallyl)-N-(2-oxoethyl)-amine.

The starting compounds of the formula (III) are known from theliterature and are, for the most part, commercially available.

Examples of precursors of the formula (III) which may be mentioned are:sarcosine, N-ethylglycine, N-propy.glycine, N-isopropylglycine,N-phenylglycine, N-benzylglycine, N-methylalanine, N-phenylalanine,N-methylphenylglycine, N-benzylphenylglycine, azetidine-2-carboxylicacid, proline, trans-4-hydroxyproline, piperidine-2-carboxylic acid,thiazolidine-4-carboxylic acid, 5,5-dimethylthiazolidine -4-carboxylicacid, sarcosine methyl ester, sarcosine ethyl ester, N-benzylglycinemethyl ester and N-benzylglycine ethyl ester.

The reaction of (II) with (III) by the process according to theinvention is carried out in a solvent. Hydrocarbons such as benzene,toluene, xylenes or tetralin, ethers such as dioxane, dibutyl ether,dimethoxyethane, diethylene glycol dimethyl ether, diethylene glycoldiethyl ether, alcohols such as butanol, pentanol, ethylene glycol,ethylene glycol monomethyl ether and ethylene glycol monoethyl ether,and dipolar aprotic solvents such as dimethylformamide, dimethylsulphoxide, N-methylpyrrolidone and sulpholane can be used. Toluene,xylenes and dimethylformamide are particularly preferred.

The reaction temperature can be varied within a relatively wide range.In general, the reactions are carried out between 20° C. and 200° C.,preferably between 80° C. and 150° C.

The reaction can be carried out at normal pressure, but also at elevatedpressure. In general, the reaction is carried out at pressures betweenabout 1 bar and 100 bar, preferably between about 1 bar and 10 bar.

When carrying out the process according to the invention, 0.5 to 6moles, preferably 0.5 to 2 moles, of amino acid derivative (III) areemployed per mole of unsaturated carbonyl compound (II).

The reaction can be carried out by adding the unsaturated carbonylcompound dropwise to a suspension or solution of the amino acidderivative (III) in one of the solvents indicated. However, bothcomponents can also be initially introduced in a solvent and thereaction can be carried out in the temperature range indicated. Thewater of reaction set free in the reaction can be distilled off with thesolvent as an azeotrope. The course of the reaction can easily befollowed by the evolution of CO₂ which occurs. Working up is carriedout, if appropriate after separating off unreacted amino acid (III), byremoving the solvent and distillation. It is also possible to extractthe basic products from the organic solvent using an acid, such as, forexample hydrochloric acid, in order to separate off neutral impurities.

In a further step of the process according to the invention, thesubstituents R² and R⁶, if they have a protective group function, can beremoved.

Acyl radicals are removed by hydrolysis. Strong acids or strong basesare suitable for the hydrolysis. Aqueous hydrochloric acid, hydrobromicacid or trifluoroacetic acid are preferably used for the acidichydrolysis. The basic hydrolysis is carried out using alkali metalhydroxides or alkaline earth metal hydroxides, lithium hydroxide, sodiumhydroxide, potassium hydroxide, calcium hydroxide and barium hydroxidebeing preferred. Solvents used are water and alcohols, water, ethanol ormixtures of these solvents being preferred. The hydrolysis can becarried out at temperatures between 0° and 200° C., preferably between20° and 140° C. Pressures between about 1 bar and 100 bar are used here,preferably between about 1 bar and 10 bar.

If the radicals R² or R⁶ are benzyl radicals, these radicals can beremoved by hydrogenolysis. Water, alcohols, carboxylic acids, alcoholichydrochloric acid, cyclic ethers or mixtures thereof can be used assolvents. Catalysts used are palladium, both as a sponge and on supportssuch as active carbon, calcium carbonate or barium sulphate, andpalladium hydroxide on active carbon. The reaction is carried out attemperatures between about 0° and 200° and hydrogen pressures from 1 barto 200 bar.

The process according to the invention moreover comprises the conversionof the radicals R² and R⁶, if these are acyl radicals, into alkylradicals by reduction. The reduction can be carried out bothcatalytically and using hydrides or complex hydrides of the elements ofthe third main group. The reduction is preferably carried out usingdiborane, lithium aluminum hydride and sodium borohydride, in the lastcase with the addition of Lewis acids such as titanium tetrachloride,aluminum trichloride or boron trifluoride.

The reaction is carried out in inert organic solvents such as ethers,for example diethyl ether, dibutyl ether, methyl tert.-butyl ether,tetrahydrofuran, dioxane or ethylene glycol dimethyl ether orhydrocarbons such as toluene or xylene. The temperatures can be variedbetween about 0° and 200° C. In order to attain high reactiontemperatures, the reaction can be carried out at pressures up to 100bar.

Preferably, the reduction is carried out using lithium aluminum hydrideor sodium borohydride/boron trifluoride etherate in tetrahydrofuran ordioxane at the reflux temperature of the solvent.

The compounds according to the invention are used as starting substancesfor antibacterially active quinolone- or naphthyridonecarboxylic acids.

Thus, for example,8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacidcan be reacted with 2-methyl-2,7-diazabicyclo[3.3.0]octane to give8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3-quinolinecarboxylicacid, which has a high antibacterial activity.

EXAMPLE 1 2,7-Diazabicyclo[3.3.0]octane a) EthylN-(2,2-dimethoxyethyl)-carbamate H₅ C₂ OOC--NH--CH₂₋₋ CH(OCH₃)₂

214 g (2 mol) of ethyl chloroformate are added dropwise at 10° C. to 214g (2 mol) of aminoacetaldehyde dimethyl acetal in 1 1 of toluene and 90g of NaOH in 500 ml of water. The mixture is stirred for a further 2hours at room temperature, and the aqueous phase is separated off,saturated with sodium chloride and extracted using toluene. The toluenesolutions are dried over magnesium sulphate, concentrated and distilled.

Yield: 338 g (95.4% of theory).

Boiling point: 60° C./0.03 mbar.

b) Ethyl N-allyl-N-(2,2-dimethoxyethyl)-carbamate ##STR14##

500 g (2.82 mol) of ethyl N-(2,2-dimethoxyethyl)carbamate, 625 g ofpowdered potassium hydroxide and 10 g of triethylbenzylammonium chlorideare initially introduced into 2.7 1 of toluene and 345 g (2.85 mol) ofallyl bromide are added dropwise at room temperature. The mixture isstirred overnight at room temperature, the salts are filtered off withsuction, and the filtrate is washed once with saturated sodium chloridesolution, dried over potassium carbonate, concentrated and distilled.

Yield: 582 g (95% of theory).

Boiling point: 64° C./0.1 mbar.

c) Ethyl N-allyl-N-(2-oxoethyl)-carbamate ##STR15##

68 g (0.313 mol) of ethyl N-allyl-N-(2,2-dimethoxyethyl) -carbamate areheated at 100° C. for an hour with 150 ml of formic acid. The mixture ispoured onto ice, extracted several times with methylene chloride, andthe organic phases are washed with sodium hydrogen carbonate solution,dried over magnesium sulphate, concentrated and distilled.

Yield: 46.7 g (87.2% of theory).

Boiling point: 58° C./0.09 mbar.

d) N-Benzylglycine ##STR16##

225.8 g (1.17 mol) of N-benzylglycine ethyl ester (J. Am. Chem. Soc. 72,1238 (1950)) are heated under reflux overnight in 600 ml of water.Product which has crystallized out is filtered off with suction and thefiltrate is extracted once with tert.-butyl methyl ether. The aqueousphase is concentrated and the crystals obtained are dried overphosphorus pentoxide in a desiccator together with the product filteredoff.

Yield: 184 g (95% of theory).

Melting point: 199° C.

e) Ethyl 2-benzyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate ##STR17##

42.8 g (0.25 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heatedunder reflux overnight with 41.3 g (0.25 mol) of N-benzylglycine in 750ml of toluene. The mixture is concentrated and the residue is distilled.

Yield: 59.6 g (87% of theory).

Boiling point: 140° C./0.09 mbar.

f) Ethyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate ##STR18##

21.2 g (77.3 mmol) of ethyl2-benzyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 400 ml ofethanol are hydrogenated at 100° C. and 100 bar on 3 g ofpalladium-active carbon (10% Pd). The catalyst is filtered off, thefiltrate is concentrated and the residue is distilled.

Yield: 10.3 g (72.3% of theory).

Boiling point: 82-92° C./0.1 mbar.

g) 2,7-Diazabicyclo[3.3.0]octane ##STR19##

9 g (48.8 mmol) of ethyl 2,7-diazabicyclo[3.3.0]-octane-7-carboxylateare heated under reflux overnight with 32 g (100 mmol) of Ba(OH)₂. 8H₂ Oin 140 ml of water. The mixture is saturated with potassium carbonate,barium carbonate is filtered off with suction and the filtrate isextracted ten times with 100 ml of chloroform each time. The extract isdried over potassium carbonate and concentrated, and the residue isdistilled.

Yield: 3.4 g (62% of theory).

Boiling point: 70° C./6 mbar.

EXAMPLE 2 2-Benzyl-2,7-diazabicyclo[3.3.0]octane ##STR20##

55.6 g (0.2 mol) of ethyl 2-benzyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 300ml of concentrated hydrochloric acid. The mixture is then renderedalkaline with potassium carbonate and extracted five times with 100 mlof chloroform each time, the extracts are dried over potassium carbonateand concentrated, and the residue is distilled.

Yield: 31 g (76.6% of theory).

Boiling point: 105° C./0.45 mbar.

EXAMPLE 3 Ethyl 2.7-diazabicyclo[3.3.0]octane-2-carboxylate a)tert.-Butyl 2-benzyldiazabicyclo[3.3.0]octane-7-carboxylate ##STR21##

20.2 g (0.1 mol) of 2-benzyl-2,7-diazabicyclo -[3.3.0]octane aredissolved in 125 ml of tert.-butanol, a solution of 4.2 g of sodiumhydroxide in 100 ml of water is added and 23 g (0.105 mol) ofdi-tert.-butyl pyrocarbonate are added dropwise at room temperature. Themixture is stirred overnight at room temperature and extracted fivetimes with 100 ml of chloroform each time, the extracts are dried overpotassium carbonate and concentrated, and the residue is distilled.

Yield: 24.8 g (82% of theory).

Boiling point: 145-149° C./0.8 mbar.

b) tert.-Butyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate ##STR22##

24 g (79.4 mmol) of tert.-butyl 2-benzyldiazabicyclo[3.3.0]octane-7-carboxylate in 400 ml of ethanol are hydrogenated at100° C. and 100 bar on 3 g of palladium-active carbon (10% Pd). Thecatalyst is filtered off, the filtrate is concentrated and the residueis distilled.

Yield: 13.1 g (77.7% of theory).

Boiling point: 87° C./0.1 mbar.

c) 2-Ethy17-tert.-buty12,7-diazabicyclo[3.3.0]octane -2,7-dicarboxylate##STR23##

13 g (61.2 mmol) of tert.-butyl 2,7-diazabicyclo-[3.3.0]octane-7-carboxylate are dissolved in 100 ml of toluene, asolution of 3 g of sodium hydroxide in 20 ml of water is added and 7 g(64.5 mmol) of ethyl chloroformate are added dropwise at roomtemperature. The mixture is stirred for three hours at room temperature,and the aqueous phase is separated off and extracted twice with 100 mlof methylene chloride each time. The organic solutions are dried overmagnesium sulphate and concentrated, and the residue is distilled.

Yield: 16 g (91.9% of theory).

Boiling point: 125° C./0.13 mbar.

d) Ethyl 2,7-diazabicyclo[3.3.0]octane-2-carboxylate ##STR24##

15.2 g (53.5 mmol) of 2-ethyl 7-tert.-butyl2,7-diazabicyclo[3.3.0]octane-2,7-dicarboxylate in 100 ml of chloroformare heated under reflux for five hours with 10.5 g (55.3 mol) ofpara-toluenesulphonic acid. The mixture is washed with 50 ml of 10%strength sodium hydroxide solution, the organic phase is dried overpotassium carbonate and concentrated, and the residue is distilled.

Yield: 9.5 g (96.4% of theory).

Boiling point: 80-90° C./0.1 mbar.

EXAMPLE 4 2-Methyl-2,7-diazabicyclo[3.3.0]octane a) Ethyl2-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate ##STR25##

8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heatedunder reflux overnight with 4.5 g (50 mmol) of sarcosine in 200 ml oftoluene. The mixture is concentrated and the residue is distilled.

Yield: 7.5 g (75.7% of theory).

Boiling point: 80-82° C./0.1 mbar.

b) 2-Methyl-2,7-diazabicyclo[3.3.0]octane ##STR26##

9 g (45.4 mmol) of ethyl 2-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 50 mlof concentrated hydrochloric acid. The mixture is rendered alkaline withpotassium carbonate, extracted ten times using 50 ml of chloroform eachtime, dried over potassium carbonate and concentrated, and the residueis distilled.

Yield: 4.5 g (78% of theory).

Boiling point: 72° C./25 mbar.

EXAMPLE 5 2-Phenyl-2,7-diazabicyclo[3.3.0]octane a) Ethyl2-phenyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate ##STR27##

8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate and 7.6 50mmol) of phenylglycine are heated under reflux overnight in 200 ml oftoluene. The mixture is decanted from resinous material andconcentrated, and the residue is distilled.

Yield: 8.1 g (62.2% of theory).

Boiling point: 151° C./0.12 mbar.

b) 2-Phenyl-2,7-diazabicyclo[3.3.0]octane ##STR28##

7.6 g (31.6 mmol) of ethyl 2-phenyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 50 mlof concentrated hydrochloric acid. The mixture is concentrated, theresidue is taken up in 50 ml of 10% strength sodium hydroxide solutionand the mixture is extracted five times using 50 ml of chloroform eachtime. The extracts are dried over potassium carbonate and concentrated,and the residue is distilled.

Yield: 3.7 g (62% of theory).

Boiling point: 103° C./0.08 mbar.

EXAMPLE 6 3-Methyl-2,7-diazabicyclo[3.3.0]octane a) N-Benzylalanine##STR29##

333 g (1.72 mmol) of N-benzylalanine methyl ester (J. Chem. Soc. 4374(1952)) are heated under reflux overnight with 860 ml of water. Productwhich has deposited is filtered off with suction and the filtrate isextracted once with tert.-butyl methyl ether. The aqueous solution isconcentrated and the crystals obtained are dried over phosphoruspentoxide in a desiccator with the first crystal fraction.

Yield 280 g (91% of theory).

Melting point: 270-276° C. (decomposition).

b) Ethyl 2-benzyl-3-methyl-2,7-diazabicyclo[3.3.0]-octane-7-carboxylate##STR30##

42.8 (0.25 mol) of ethyl N-allyl-N-(2-oxo -ethyl)-carbamate are heatedunder reflux overnight with 44.8 g (0.25 mol) of N-benzylalanine in 750ml of toluene. The mixture is concentrated and the residue is distilledtwice.

Yield: 32 g (44.4% of theory).

Boiling point: 128-133° C./0.06 mbar.

The product consists to 96% of a stereoisomer.

c) Ethyl 3-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate ##STR31##

32 g (0.11 mol) of ethyl2-benzyl-3-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 560 mlof ethanol are hydrogenated at 100° C. and 100 bar on 4.5 g ofpalladium-active carbon. The catalyst is filtered off with suction, thefiltrate is concentrated and the residue is distilled.

Yield: 17.1 g (77.7% of theory).

Boiling point: 140-145° C./8 mbar.

d) 3-Methyl-2,7-diazabicyclo[3.3.0]octane ##STR32##

17 g (85.7 mmol) of ethyl .3-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 100ml of concentrated hydrochloric acid. The mixture is concentrated, theresidue is taken up in 50 ml of water, rendered alkaline with potassiumcarbonate and extracted ten times using 50 ml of chloroform each time.The extracts are dried over potassium carbonate and concentrated, andthe residue is distilled.

Yield: 6 g (55% of theory).

Boiling point: 68-70° C./6 mbar.

EXAMPLE 7 2,3-Dimethyl-2,7-diazabicyclo[3.3.0]octane a) Ethyl2,3-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate ##STR33##

17.2 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heatedunder reflux overnight with 10.5 g (0.1 mol) of N-methylalanine in 300ml of toluene. The mixture is concentrated and the residue is distilled.

Yield: 11.3 g (53.2% of theory).

Boiling point: 81° C./0.25 mbar.

b) 2,3-Dimethyl-2,7-diazabicyclo[3.3.0]octane ##STR34##

7.25 g (34.2 mmol) of ethyl2,3-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heatedunder reflux overnight with 50 ml of concentrated hydrochloric acid. Themixture is rendered alkaline with potassium carbonate and extracted tentimes using 50 ml of chloroform each time, the extracts are dried overpotassium carbonate and concentrated, and the residue is distilled.

Yield: 3 g (62.5% of theory).

Boiling point: 72-74° C./10 mbar.

EXAMPLE 8 2,8-Dimethyl-2,7-diazabicyclo[3.3.0]octane a) EthylN-(1,1-dimethoxyprop-2-yl)-carbamate ##STR35##

80 g (0.73 mol) of ethyl chloroformate are added dropwise withice-cooling to 86.2 g (0.72 mol) of 2-aminopropionaldehyde dimethylacetal in 350 ml of toluene and 32 g (0.8 mol) of NaOH in 300 ml ofwater. The mixture is stirred for a further 2 hours at room temperature,the organic phase is separated off, the aqueous phase is extracted usingtoluene and the toluene solutions are dried over K₂ CO₃. The extractsare concentrated and the residue is distilled.

Yield: 132 g (95% of theory).

Boiling point: 55° C./0.06 mbar.

b) Ethyl N-allyl-N-(1,1-dimethoxyprop-2-yl)-carbamate ##STR36##

151 g (0.79 mol) of ethyl N-(1,1-dimethoxyprop 2-yl)-carbamate, 175 g ofpowdered potassium hydroxide and 2.8 g of triethylbenzylammoniumchloride are initially introduced into 750 ml of toluene and 94 g (0.777mol) of allyl bromide are added dropwise at room temperature. Afterstirring overnight at room temperature, a further 10 g (82.6 mmol) ofallyl bromide are added dropwise and the mixture is stirred for one dayat room temperature. Water is added until all salts have gone intosolution, and the aqueous phase is separated off and extracted twicewith 150 ml of toluene each time. The extracts are dried over K₂ CO₃ andconcentrated, and the residue is distilled.

Yield: 173 g (94.7% of theory).

Boiling point: 68° C./0.1 mbar.

c) Allyl-(1,1-dimethoxyprop-2-yl)-amine ##STR37##

20 g of molecular sieve are added to 12 g (0.1 mol) of1,1-dimethoxyacetone in 100 ml of ethanol and 7 g (0.12 mol) ofallylamine are then added dropwise. The mixture is allowed to standovernight at room temperature, decanted from the molecular sieve andcooled in an ice-bath to 0° C., and 4 g (0.1 mol) of sodium borohydrideare added in small portions. The mixture is stirred overnight at roomtemperature and concentrated, the residue is taken up in 100 ml ofwater, and the mixture is saturated with potassium carbonate andextracted five times with 100 ml of chloroform each time. The extractsare dried over potassium carbonate and concentrated, and the residue isdistilled.

Yield: 10.3 g (64.7% of theory).

Boiling point: 75° C./25 mbar.

d) Ethyl N-allyl-N-(1,1-dimethoxyprop-2-yl)-carbamate ##STR38##

125 g (0.785 mol) of allyl-(1,1-dimethoxyprop-2-yl)amine are initiallyintroduced into 400 ml of toluene, a solution of 40 g of sodiumhydroxide in 200 ml of water is added, the mixture is cooled in anice-bath to 0° C. and 95 g (0.876 mol) of ethyl chloroformate are addeddropwise. The mixture is then stirred for 3 hours at room temperature,and the aqueous phase is separated off and extracted twice using 100 mlof toluene each time. The extracts are dried over potassium carbonateand concentrated, and the residue is distilled.

Yield: 170.8 g (94% of theory).

Boiling point: 55° C./0 05 mbar.

e) Ethyl N-allyl-N-(1-oxoprop-2-yl)-carbamate ##STR39##

182 g (0.7S7 mol) of ethyl N-allyl-N-(1,1-dimethoxyprop -2-yl)-carbamatein 1.5 1 of water are heated under reflux for three hours with 80 ml offormic acid. The mixture is saturated with sodium chloride, the organicphase is separated off and the aqueous phase is extracted twice with 500ml of methylene chloride each time. The organic solutions are washedwith saturated sodium hydrogen carbonate solution until neutral, driedover magnesium sulphate and concentrated, and the residue is distilled.

Yield: 134 g (91.9% of theory).

Boiling point: 65 C/0.23 mbar.

f) Ethyl 2,8-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate##STR40##

18.5 g (0.1 mol) of ethyl N-allyl-N-(1-oxoprop -2-yl)-carbamate areheated under reflux overnight in a water separator with 9 g (0.1 mol) ofsarcosine in 300 ml of toluene. The mixture is concentrated and theresidue is distilled.

Yield: 17 g (80% of theory).

Boiling point: 140-150° C./8 mbar.

g) 2,8-Dimethyl-2,7-diazabicyclo[3.3.0]octane ##STR41##

16.9 g (79.6 mol) of ethyl2,8-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heatedunder reflux overnight with 130 ml of concentrated hydrochloric acid.The mixture is concentrated, the residue is taken up in 50 ml of water,and the mixture is rendered alkaline with potassium carbonate andextracted five times using 50 ml of chloroform each time. The extractsare dried over potassium carbonate and concentrated, and the residue isdistilled.

Yield: 6.6 g (58.5% of theory).

Boiling point: 60-62° C./6 mbar.

EXAMPLE 9 5-Chloro-2-methyl-2,7-diazabicyclo[3.3.0]octane a) EthylN-(2-chloroallyl)-N-(2,2-dimethoxyethyl) -carbamate ##STR42##

115 g (0.65 mol) of ethyl N-(2,2-dimethoxyethyl) -carbamate, 130 g ofpowdered potassium hydroxide and 2 g of triethylbenzylammonium chlorideare initially introduced into 650 ml of toluene and 142 g (0.7 mol) of2-chloroallyl iodide are added dropwise at room temperature. Afterstirring overnight, a gas chromatogram showed incomplete conversion,hence 65 g of powdered potassium hydroxide and 1 g oftriethylbenzylammonium chloride were added again and a further 71 g(0.35 mol) of 2-chloroallyl iodide were added dropwise. After stirringovernight at room temperature, the salts were filtered off with suction,the filtrate was washed with saturated sodium chloride solution, driedover magnesium sulphate and concentrated, and the residue was distilled.

Yield: 140.9 g (86% of theory).

Boiling point: 92-97° C./0.8 mbar.

b) Ethyl N-(2-chloroallyl)-N-(2-oxoethyl)-carbamate ##STR43##

151 g (0.6 mol) of ethyl N-(2-chloroallyl)-N-(2,2-dimethoxyethyl)-carbamate are heated under reflux for 3 hours with60 ml of formic acid in 1.2 1 of water. The mixture is saturated withsodium chloride, and the aqueous phase is separated off and extractedtwice with 300 ml of methylene chloride each time. The organic phasesare washed with saturated sodium hydrogen carbonate solution untilneutral, dried over magnesium sulphate and concentrated, and the residueis distilled.

Yield: 97.1 g (78% of theory).

Boiling point: 88-91° C./0.06 mbar.

c) Ethyl 5-chloro-2-methyl-2,7-diazabicyclo[3.3.0]-octane-7-carboxylate##STR44##

10.3 g (50mmol) of ethyl N-(2-chloroallyl)-N-(2-oxoethyl)-carbamate areheated under reflux overnight with 4.5 g (50 mmol) of sarcosine in 200ml of toluene. The mixture is concentrated and the residue is distilled.

Yield: 10.6 g (91% of theory).

Boiling point: 80° C./0.1 mbar.

d) 5-Chloro-2-methyl-2,7-diazabicyclo[3.3.01]octane ##STR45##

9.3 g (40 mmol) of ethyl5-chloro-2-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heatedunder reflux overnight with 50 ml of concentrated hydrochloric acid. Themixture is concentrated, the residue is taken up in 30 ml of water, andthe mixture is rendered alkaline with potassium carbonate and extractedfive times with 50 ml of chloroform each time. The extracts are driedover potassium carbonate and concentrated, and the residue is distilled.

Yield: 4.7 g (72% of theory).

Boiling point: 73° C./4 mbar.

EXAMPLE 10 5-Chloro-2,3-dimethyl-2,7-diazabicyclo[3.3.0]octane a) Ethyl5-chloro-2,3-dimethyl-2,7-diazabicyclo[3.3.0]-octane-7-carboxylate##STR46##

10.3 g (50 mmol) of ethyl N-(2-chloroallyl)-N-(2 -oxoethyl)-carbamateare heated under reflux overnight with 5.2 g (50.5 mmol) ofN-methylalanine in 200 ml of toluene. The mixture is concentrated andthe residue is distilled.

Yield: 8.1 g (65.7% of theory).

Boiling point: 87° C./0.08 mbar.

b) 5-Chloro-2,3-dimethyl-2,7-diazabicyclo[3.3.0]octane ##STR47##

7.6 g (30.8 mmol) of ethyl 5-chloro-2,3-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under refluxovernight with 30 ml of concentrated hydrochloric acid. The mixture isconcentrated, the residue is taken up in 30 ml of water, and the mixtureis rendered alkaline with potassium carbonate, extracted five times with50 ml of chloroform each time, dried over potassium carbonate andconcentrated, and the residue is distilled.

Yield: 3.7 g (68.4% of theory).

Boiling point: 95-97° C./6 mbar.

EXAMPLE 11 1,4-Diazatricyclo[6.2.0.0²,6 ]decane a) Ethyl1,4-diazatricyclo[6.2.0.0²,6 ]decane-4-carboxylate ##STR48##

17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heatedunder reflux overnight in a water separator with 10 g (0.1 mol) ofazetidine-2-carboxylic acid in 200 ml of toluene. Unreacted amino acidis filtered off with suction, the filtrate is concentrated and theresidue is distilled.

Yield: 13.8 g (65.6% of theory).

Boiling point: 108° C./0.35 mbar.

b) 1,4-Diazatricyclo[6.2.0.0²,6 ]decane ##STR49##

13.7 g (65.1 mmol) of ethyl 1,4-diazatricyclo [6.2.0.0²,6]decane-4-carboxylate are heated under reflux overnight with 42 g ofBa(OH)₂. 8H₂ O in 150 ml of water. Potassium carbonate is added, bariumcarbonate is filtered off with suction and the filtrate is extracted tentimes using 100 ml of chloroform each time. The extracts are dried overpotassium carbonate and concentrated, and the residue is distilled.

Yield: 5.3 g (58.9% of theory).

Boiling point: 85° C./6 mbar.

EXAMPLE 12 1,4-Diazatricyclo[6.3.0.0²,6 ]undecane a) Ethyl1,4-diazatricyclo[6.3.0.0²,6 ]undecane-4-carboxylate ##STR50##

8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heatedunder reflux overnight with 5.8 g (50 mmol) of proline in 200 ml oftoluene. The mixture is concentrated and the residue is distilled.

Yield: 9.6 g (86% of theory).

Boiling point: 102-112° C./0.13-0.15 mbar.

b) 1,4-Diazatricyclo[6.3.0.0²,5 ]undecane ##STR51##

9 g (40 mmol) of ethyl 1,4-diazatricyclo -[6.3.0.0²,6]undecane-4-carboxylate are heated under reflux overnight with 50 ml ofconcentrated hydrochloric acid. The mixture is rendered alkaline withpotassium carbonate and extracted ten times using 50 ml of chloroformeach time, the extracts are dried over potassium carbonate andconcentrated, and the residue is distilled.

Yield: 4.9 g (80.5% of theory).

Boiling point: 50° C./0.05 mbar.

EXAMPLE 13 10-Hydroxy-1,4-diazatricyclo[6.3.0.0²,6 ]undecane a) Ethyl10-hydroxy-1,4-diazatricyclo[6.3.0.0²,6 ]-undecane-4-carboxylate##STR52##

8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated at120° C. overnight with 6.6 g (50 mmol) of trans-4-hydroxyproline in 200ml of dimethylformamide. The mixture is concentrated and the residue isdistilled.

Yield: 9.7 g (81% of theory).

Boiling point: 170° C./0.3 mbar.

The product consists predominantly of two stereoisomers in the ratio1:1.

b) 10-Hydroxy-1,4-diazatricyclo[6.3.0.0²,6 ]undecane ##STR53##

8 g (33.3 mmol) of ethyl 10-hydroxy-1,4-diazatricyclo[6.3.0.0²,6]undecane-4-carboxylate are heated under reflux overnight with 21 g ofBa(OH)₂. 8H₂ O in 150 ml of water. The mixture is saturated withpotassium carbonate, barium carbonate is filtered off with suction andthe filtrate is extracted ten times using 100 ml of chloroform eachtime. The extracts are dried over potassium carbonate and concentrated,and the residue is distilled.

Yield: 4.6 g (82% of theory).

Boiling point: 110-115° C./0 1 mbar.

EXAMPLE 14 1,4-Diazatricyclo[6.4.0.0²,6 ]dodecane a) Ethyl1,4-diazatricyclo[6.4.0.0²,6 ]dodecane-4-carboxylate ##STR54##

17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heatedunder reflux overnight with 13 g (0.1 mol) of piperidine-2-carboxylicacid in 200 ml of toluene. The mixture is concentrated and the residueis distilled.

Yield: 20.8 g (87.2% of theory).

Boiling point: 105-112° C./0.12 mbar.

b) 1,4-Diazatricyclo[6.4.0.0²,6 ]decane ##STR55##

20.7 g (86.8 mmol) of ethyl 1,4-diazatricyclo -[6.4.0.0²,6]dodecane-4-carboxylate are heated under reflux overnight with 250 ml ofconcentrated hydrochloric acid. The mixture is concentrated, the residueis taken up in 50 ml of water and the mixture is rendered alkaline withpotassium carbonate. It is extracted ten times using 50 ml of chloroformeach time, the extracts are dried over potassium carbonate andconcentrated, and the residue is distilled.

Yield: 8.5 g (58.9% of theory).

Boiling point: 108° C./8 mbar.

EXAMPLE 15 10-Thia-1,4-diazatricyclo[6.3.0.0²,6 ]undecane a) Ethyl10-thia-1,4-diazatricyclo[6.3.0.0²,6 ]undecane -4-carboxylate ##STR56##

17.2 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heatedunder reflux overnight with 13.5 g (0 1 mol) ofthiazolidine-4-carboxylic acid in 300 ml of toluene. The mixture isconcentrated and the residue is distilled.

Yield: 20 g (82.5% of theory).

Boiling point: 155-156° C./0.5 mbar.

b) 10-Thia-1,4-diazatricyclo[6.3.0.0²,6 ]undecane ##STR57##

12.5 g (50 mmol) of ethyl 10-thia-1,4-diazatricyolo[6.3.0.0²,6]undecane-4-carboxylate are heated under reflux overnight with 32 g ofBa(OH)₂. 8H₂ O in 225 ml of water. Potassium carbonate is added to themixture, barium carbonate is filtered off with suction and the filtrateis extracted ten times using 100 ml of chloroform each time. Theextracts are dried over potassium carbonate and concentrated, and theresidue is distilled.

Yield: 6.2 g (72.8% of theory).

Boiling point 90-94° C./0.05 mbar.

EXAMPLE 16 9,9-Dimethyl-10-thia-1,4-diazatricyclo[6.3.0.0²,6 ]undecanea) Ethyl 9,9-dimethyl-10-thia-1,4-diazatricyclo -[6.3.0.0²,6]-undecane-4-carboxylate ##STR58##

8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heatedunder reflux overnight with 8.1 g (50 mmol) of5,5-dimethylthiazolidine-4-carboxylic acid in 200 ml of toluene. Themixture is concentrated and the residue is distilled.

Yield: 8.4 g (62.2% of theory).

Boiling point: 141-155° C./0.03-0.05 mbar.

b) 9,9-Dimethyl-10-thia-1,4-diazatricyclo[6.3.0.0²,6 ]-undecane##STR59##

6 g (22.2 mmOl) of ethyl 9,9-dimethyl-10-thia-1,4-diazatricyclo[6.3.0.0²,6 ]undecane-4-carboxylate are heated underreflux overnight with 12 g of Ba(OH)₂. 8H₂ O in 100 ml of water.Potassium carbonate is added, barium carbonate is filtered off withsuction and the filtrate is extracted ten times using 100 ml ofchloroform each time. The extracts are dried over potassium carbonateand concentrated, and the residue is distilled.

Yield: 2.25 g (51% of theory).

Boiling point: 83° C./0.02 mbar.

EXAMPLE 17 7-Methyl-2,7-diazabicyclo[3.3.0]octane a)2-Benzyl-7-methyl-2,7-diazabicyclo[3.3.0]octane ##STR60##

13.7 g (50 mmol) of ethyl 2-benzyldiazabicyclo-[3.3.0]octane-7-carboxylate in 20 ml of absolute tetrahydrofuran areadded dropwise to 3.8 g (0.1 mol) of lithium aluminum hydride in 100 mlof absolute tetrahydrofuran. The mixture is heated under refluxovernight and decomposed successively with 4 ml each of water, 15%strength potassium hydroxide solution and water. The inorganic salts arefiltered off with suction and boiled three times with 50 ml oftetrahydrofuran each time. The organic solutions are concentrated andthe residue is distilled.

Yield: 10.4 g (96% of theory).

Boiling point: 90-100° C./0.1 mbar.

b) 7-Methyl-2.7-diazabicyclo[3.3.0octane ##STR61##

10.3 g (47.6 mmol) of 2-benzyl-7-methyl-2,7 -diazabicyclo[3.3.0]octanein 200 ml of ethanol are hydrogenated at 100° C. and 100 bar on 2.5 g ofpalladium-active carbon (10% Pd). The catalyst is filtered off withsuction, the filtrate is concentrated and the residue is distilled.

Yield: 4.2 g (69.9% of theory).

Boiling point: 50-53° C./6 mbar.

EXAMPLE 18 Benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane a) Ethyl2-benzyl-8-methyl-2,7-diazabicyclo[3.3.0]-octane-7-carboxylate ##STR62##

37 g (0.2 mol) of ethyl N-allyl-N-(1-oxo-2-propyl)-carbamate are heatedunder reflux overnight in a water separator with 33 g (0.2 mol) ofN-benzylglycine in 500 ml of toluene. The mixture is concentrated andthe residue is distilled.

Yield: 48.5 g (84% of theory).

Boiling point: 140-145° C./0.2 mbar.

The product is a homogeneous stereoisomer by gas chromatography.

b) 2-Benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane ##STR63##

16 g (55 mmol) of ethyl2-benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heatedunder reflux overnight with 50 ml of concentrated hydrochloric acid. Themixture is concentrated, and the residue is dissolved in 50 ml of waterand rendered alkaline with potassium carbonate. The mixture is extractedfive times using 50 ml of chloroform each time, the extracts are driedover K₂ CO₃ and concentrated, and the residue is distilled.

Yield: 7.9 g (66.4% of theory).

Boiling point: 108-113° C./0.17 mbar.

EXAMPLE 19 8-Methyl-2,7-diazabicyclo[3.3.0]octane ##STR64##

7.8 g (36 mmol) of 2-benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane in200 ml of ethanol are hydrogenated at 100° C. and 100 bar on 2 g ofpalladium-active carbon (10% Pd). The catalyst is filtered off withsuction, the filtrate is concentrated and the residue is distilled. Thedistillate crystallizes.

Yield: 3.3 g (72.7% of theory).

Boiling point: 110° C./30 mbar.

Melting point: 72-75° C.

EXAMPLE 20 Ethyl 8-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate##STR65##

16 g (55 mmol) of ethyl2-benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 300 mlof ethanol are hydrogenated at 100° C. and 100 bar on 3 g ofpalladium-active carbon (10% Pd). The catalyst is filtered off withsuction, the filtrate is concentrated and the residue is distilled.

Yield: 9.7 g (89% of theory).

Boiling point: 100° C./0.1 mbar.

EXAMPLE 21 7,8-Dimethyl-2,7-diazabicyclo[3.3.0]octane a)2-Benzyl-7,8-dimethyl-2,7-diazabicyclo[3.3.0octane ##STR66##

14.4 g (50 mmol) of ethyl2-benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 20 mlof absolute tetrahydrofuran are added dropwise to 3.8 g (0.1 mol) oflithium aluminum hydride in 100 ml of absolute tetrahydrofuran and themixture is then heated under reflux overnight. It is decomposedsuccessively using 4 ml each of water, 15% strength potassium hydroxidesolution and water, and the inorganic salts are filtered off withsuction and boiled three times with 50 ml of tetrahydrofuran each time.The organic solutions are concentrated and the residue is distilled.

Yield: 10.9 g (94.6% of theory).

Boiling point: 105° C./0.08 mbar.

b) 7.8-Dimethyl-2,7-diazabicyclo[3.3.0]octane ##STR67##

10.8 g (46.9 mmol) of2-benzyl-7,8-dimethyl-2,7-diazabicyclo[3.3.0]octane in 200 ml of ethanolare hydrogenated at 100° C. and 100 bar on 2.5 g of palladium-activecarbon. The catalyst is filtered off with suction, the filtrate isconcentrated and the residue is distilled.

Yield: 4.3 g (65.4% of theory).

Boiling point: 60-62° C./6 mbar.

EXAMPLE 22 4-Methyl-2,7-diazabicyclo[3.3.0]octane a)N-(2-Buten-1-yl)-N-(2,2-dimethoxyethyl)-amine ##STR68##

200 g of molecular sieve are initially introduced into 1,000 ml ofethanol and 105 g (1 mol) of aminoacetaldehyde dimethyl acetal and 70 g(1 mol) of crotonaldehyde are added. The mixture is allowed to stand atroom temperature overnight, decanted off from molecular sieve and cooledto 0° C., and 40 g of sodium borohydride are added in 1 g portions. Themixture is then stirred overnight at room temperature and concentrated,the residue is taken up in 500 ml of water and potassium carbonate isadded until an organic phase separates. This is extracted usingchloroform, dried over potassium carbonate and concentrated, and theresidue is distilled.

Yield: 69.5 g (41.5% of theory).

Boiling point: 85° C./12 mbar.

b) Ethyl N-(2-buten-1-yl)-N-(2,2-dimethoxyethyl) -carbamate ##STR69##

69 g (0.41 mol) of N-(2-buten-1-yl)-N-(2,2-dimethoxyethyl)-amine aredissolved in 200 ml of toluene, 30 ml of 45% strength sodium hydroxidesolution are added and 43 g (0.44 mol) of ethyl chloroformate are addeddropwise with ice-cooling. The mixture is stirred for a further threehours at room temperature, and the aqueous phase is separated off andextracted with 100 ml of toluene. The extract is dried over potassiumcarbonate and concentrated, and the residue is distilled.

Yield: 92 g (94% of theory).

Boiling point: 72° C./0.08 mbar.

Alternatively 90 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl) -carbamateare dissolved in 500 ml of toluene, 100 g of powdered potassiumhydroxide and 1.5 g of triethylbenzylammonium chloride are added and 80g (0.6 mol) of crotyl bromide (isomer mixture) are added dropwise. Themixture is stirred overnight at room temperature, the salts aredissolved in water, and the aqueous phase is separated off and extractedonce using 100 ml of toluene. The extract is dried over potassiumcarbonate and concentrated, and the residue is distilled.

Yield: 112 g (96.8% of theory).

Boiling point: 65° C./0.1 mbar.

c) Ethyl N-(2-buten-1-yl)-N-(2-oxoethyl)-carbamate ##STR70##

111 g (0.48 mol) of ethyl N-(2-buten-1-yl)-N-(2,2-dimethoxyethyl)-carbamate are heated under reflux for three hourswith 50 g of formic acid in 950 ml of water. The mixture is saturatedwith sodium chloride and extracted three times using 200 ml of methylenechloride each time. The organic phases are washed with sodium hydrogencarbonate solution until neutral, dried over magnesium sulphate andconcentrated, and the residue is distilled.

Yield: 77 g (86.6% of theory).

Boiling point: 94 to 100° C./0.15 mbar.

d) Ethyl 2-benzyl-4-methyl-2,7-diazabicyclo[3.3.0]-octane-7-carboxylate##STR71##

18.5 g (0.1 mol) of ethyl N-(2-buten-1-yl)-N-(2-oxoethyl)-carbamate areheated under reflux overnight in a water separator with 16.5 g (0.1 mol)of N-benzylglycine in 300 ml of toluene. The mixture is concentrated andthe residue is distilled.

Yield: 10 g (25% of theory).

Boiling point: 135 to 142° C./0.1 mbar.

The product is 76% pure by gas chromatography.

e) 2-Benzyl-4-methyl-2,7-diazabicyclo[3.3.0]octane ##STR72##

10 g (26.3 mmol) of ethyl2-benzyl-4-methyl-2,7-diazabicyclo[[3.3.0]]octane-7-carboxylate areheated under reflux overnight with 100 ml of concentrated hydrochloricacid. The mixture is concentrated, the residue is taken up in 20 ml ofwater, the mixture is rendered alkaline with potassium carbonate andextracted five times using 50 ml of chloroform each time, the extractsare dried over potassium carbonate and concentrated, and the residue isdistilled.

Yield: 4.6 g (81% of theory).

Boiling point: 87 to 95° C./0.13 mbar.

The product is 76% pure by gas chromatography.

f) 4-Methyl-2,7-diazabicyclo[3.3.0]octane ##STR73##

4.1 g (19 mmol) of 2-benzyl-4-methyl-2,7-diazabicyclo[3.3.0]octane in 80ml of methanol are hydrogenated at 100° C. and 100 bar on 1 g ofpalladium-active carbon (10% Pd). The catalyst is filtered off withsuction, the filtrate is concentrated and the residue is distilled.

Yield: 1.2 g (50% of theory).

Boiling point: 76° C./8 mbar.

EXAMPLE 23 5-Fluoromethyl-2-methyl-2,7-diazabicyclo[3.3.0]octane a)Ethyl N-(2-fluoromethylallyl)-N-(2,2-dimethoxyethyl) -carbamate##STR74##

8 g (0.26 mol) of sodium hydride (80% pure) are initially introducedinto 200 ml of toluene and 35.8 g (0.2 mol) of ethylN-(2,2-dimethoxyethyl)-carbamate are added dropwise at 90° C. Themixture is then stirred for one hour at 90° C. and 32.6 g (0.3 mol) of1-chloro-2-fluoromethylprop-2-ene are then added dropwise. The mixtureis stirred overnight at 90° C., salts are dissolved in water, and theaqueous phase is separated off and extracted with toluene. The organicphases are dried over potassium carbonate and concentrated, and theresidue is distilled.

Yield: 28.2 g (56.6% of theory).

Boiling point: 71 to 79° C./0.07 mbar.

b) Ethyl N-(2-fluoromethylallyl)-N-(2-oxoethyl) -carbamate ##STR75##

25 g (0.1 mol) of ethyl N-(2-fluoromethylallyl)-N-(2,2-dimethoxyethyl)carbamate are heated under reflux for two hourswith 5 g of formic acid in 100 ml of water. The mixture is saturatedwith sodium chloride and extracted with methylene chloride, and theorganic phases are washed with sodium hydrogen carbonate solution untilneutral. They are dried over magnesium sulphate and concentrated, andthe residue is distilled.

Yield: 18.5 g (87% of theory).

Boiling point: 84° C./0.18 mbar.

c) Ethyl 5-fluoromethyl-2-methyl-2,7-diazabicyclo-[3.3.0]octane-7-carboxylate ##STR76##

9.1 g (43 mmol) of ethyl N-(2-fluoromethylallyl)-N-(2-oxoethyl)-carbamate are heated under reflux overnight in a waterseparator with 3.9 g (43 mmol) of powdered sarcosine in 170 ml oftoluene. The mixture is concentrated and the residue is distilled.

Yield: 7.5 g (75.8% of theory).

Boiling point: 80 to 100° C./0.25 to 0.35 mbar.

d) 5-Fluoromethyl-2-methyl-2,7-diazabicyclo[3.3.0]-octane ##STR77##

7.1 g (26 mmol) of ethyl 5-fluoromethyl-2-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under refluxovernight in 100 ml of concentrated hydrochloric acid. The mixture isconcentrated, the residue is taken up in 20 ml of water, the mixture isrendered alkaline with potassium carbonate and extracted ten times using50 ml of chloroform each time, the extracts are dried over potassiumcarbonate and concentrated, and the residue is distilled.

Yield: 0.8 g (20% of theory).

Boiling point: 34° C./0.07 mbar.

EXAMPLE 24 5-Fluoro-7-methyl-2,7-diazabicyclo[3.3.0]octane a) EthylN-(2,2-dimethoxyethyl)-N-(2-fluoroallyl) -carbamate ##STR78##

11.6 g (65.5 mmol) of ethyl N-(2,2-dimethoxyethyl)-carbamate, 15 g ofpowdered potassium hydroxide and 0.25 g of triethylbenzylammoniumchloride are initially introduced into 65 ml of toluene and 10 g (72mmol) of 2-fluoroallyl bromide are added dropwise at room temperature.The mixture is stirred overnight at room temperature, 100 ml of waterare added, and the aqueous phase is separated off and extracted using 30ml of toluene. The organic solutions are dried over magnesium sulphateand concentrated, and the residue is distilled.

Yield: 14.1 g (91.5% of theory).

Boiling point: 72.C/0.3 mbar.

b) Ethyl N-(2-fluoroallyl)-N-(2-oxoethyl)-carbamate ##STR79##

14.1 g (60 mmol) of ethyl N-(2,2-dimethoxyethyl)-N-(2-fluoroallyl)-carbamate are heated under reflux for three hourswith 6.3 ml of formic acid in 120 ml of water. The solution is saturatedwith sodium chloride and extracted several with methylene chloride, theorganic solutions are washed with saturated sodium hydrogen carbonatesolution, dried over magnesium sulphate and concentrated, and theresidue is distilled.

Yield: 9.8 g (86% of theory).

Boiling point: 80° C./0.25 mbar.

c) Ethyl 2-benzyl-5-fluoro-2,7-diazabicyclo[3.3.0]-octane-7-carboxylate##STR80##

20.8 g (0.11 mol) of ethyl N-(2-fluoroallyl)-N -(2-oxoethyl)-carbamateare heated under reflux with 19 g (0.115 mol) of N-benzylglycine in 300ml of toluene until evolution of CO₂ is complete. The mixture isconcentrated and the residue is distilled.

Yield: 16.4 g (44.8% of theory).

Boiling point: 148-152 C/0.1 mbar.

The product is 88% pure by gas chromatography.

d) 2-Benzyl5-fluoro-7-methyl-2,7-diazabicyclo[3.3.0]-octane ##STR81##

A solution of 16.4 g (49.4 mmol, 88% pure) of ethyl2-benzyl-5-fluoro-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 25 mlof absolute tetrahydrofuran is added dropwise to 4.3 g (0.11 mol) oflithium aluminum hydride in 125 ml of absolute tetrahydrofuran and themixture is then heated overnight under reflux. It is decomposedsuccessively with 4.5 ml each of water, 15% strength potassium hydroxidesolution and water, and the inorganic salts are filtered off withsuction and boiled three times with 50 ml of tetrahdrofuran each time.The organic solutions are concentrated and the residue is distilled.

Yield: 11 g (88% of theory).

Boiling point: 98-108° C./0.08 bar.

The product is 93% pure by gas chromatography.

e) 5-Fluoro-7-methyl-2,7-diazabicyclo[3.3.0]octane ##STR82##

11 g (43.7 mmol, 93% pure) of 2-benzyl-5-fluoro7-methyl-2,7-diazabicyclo[3.3.0]octane in 100 ml of ethanol arehydrogenated at 100° C. and 100 bar on 2 g of palladium-active carbon(10% Pd). The catalyst is filtered off with suction, the filtrate isconcentrated and the residue is distilled.

Yield: 4.4 g (69.8% of theory).

Boiling point: 85-90° C./25 mbar.

EXAMPLE 25 Ethyl 6-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate a)Ethyl N-(1-buten-3-yl)-N-(2,2-dimethoxyethyl) -carbamate ##STR83##

22 g (0.24 mol) of 3-chloro-1-butene are added to 35.5 g (0.2 mol) ofethyl N-(2,2-dimethoxyethyl)-carbamate and 26 g of powdered potassiumhydroxide in 400 ml of dimethylformamide and the mixture is warmedovernight. to 40° C. The salts are dissolved with water and the mixtureis extracted several times with methylene chloride. The organic extractsare dried over potassium carbonate and concentrated, and the residue isdistilled.

Yield: 28.5 g (61.6% of theory).

Boiling point: 60 C/0.08 mbar.

b) Ethyl N-(1-buten-3-yl)-N-(2-oxoethyl)-carbamate ##STR84##

28.3 g (0.122 mol) of ethyl N-(1-buten-3-yl)-N-2,2-dimethoxyethyl)-carbamate are heated at 100° C. for one hour with65 ml of formic acid. The mixture is poured onto 200 g of ice andextracted using methylene chloride, the organic extracts are washed withsaturated sodium hydrogen carbonate solution, dried over magnesiumsulphate and concentrated, and the residue is distilled.

Yield: 11.6 g (51.3% of theory).

Boiling point: 62-65° C./0.03 mbar.

c) Ethyl 2-benzyl-6-methyl-2,7-diazabicyclo[3.3.0]-octane-7-carboxylate##STR85##

11.6 g (62.6 mmol) of ethyl N-(1-buten-3-yl)-N -(2-oxoethyl)-carbamateand 10.4 g (62.6 mmol) of N -benzylglycine in 170 ml of toluene areheated under reflux overnight in a water separator. The mixture isconcentrated and the residue is distilled.

Yield: 13.7 g (75.9% of theory).

Boiling point: 140-153° C./0.1 mbar.

d) Ethyl 6-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate ##STR86##

13 g (44.9 mmol) of ethyl2-benzyl-6-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 150 mlof ethanol are hydrogenated ar 100° C. and 100 bar on 2 g ofpalladium-active carbon (10% Pd). The catalyst is filtered off, thefiltrate is concentrated and the residue is distilled.

Yield: 6.8 g (76.4% of theory).

Boiling point: 81° C./0.09 mbar.

EXAMPLE 26 Diethyl 2,7-diazabicyclo[3.3.0]octane-3,7-dicarboxylate a)Diethyl 2-benzyl-2,7-diazabicyclo[3.3.0]octane-3,7-dicarboxylate##STR87##

50 g (0.25 mol) of N-benzylglycine ethyl ester in 1 1 of toluene areheated under reflux in a water separator and 43 g (0.25 mol) of ethylN-allyl-N-(2-oxoethyl) -carbamate are added dropwise during the courseof two hours. The mixture is heated under reflux until water no longerseparates and concentrated, and the residue is distilled.

Yield: 82.1 g (94.8% of theory).

Boiling point: 160-165° C./0.05 mbar.

b) Diethyl 2,7-diazabicyclo[3.3.0]octane-3,7-dicarboxylate ##STR88##

96.5 g (0.279 mol) of diethyl2-benzyl-2,7-diazabicyclo[3.3.0]octane-3,7-dicarboxylate in 1 1 ofethanol are hydrogenated at 100 C and 100 bar on 5 g of palladium-activecarbon (10% Pd). The catalyst is filtered off with suction, the filtrateis concentrated and the residue is distilled.

Yield: 63.3 g (84.6% of theory).

Boiling point: 137-140 C/0.18-0.2 mbar.

EXAMPLE 27 (FINAL PRODUCT) ##STR89##

1.7 g (15 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.4 g (11 mmol) of2-methyl-2,7-diazabicyclo[3.3.0]-octane are added to 3 g (10 mmol) of8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid in a mixture of 30 ml of acetonitrile and 15 ml ofdimethylformamide and the mixture is heated under reflux for 1 hour. Themixture is evaporated, the residue is stirred with water and theundissolved precipitate is filtered off with suction, washed with waterand dried at 120° C. in vacuo.

Yield: 2.4 g (59% of theory). of 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-methyl-2,7-diazabicyclo[3.3.0]-oct-7-yl)-4-oxo-3-quinolinecarboxylicacid, melting point: 208-213° C. (with decomposition) (from glycolmonomethyl ether).

It is understood that the specification and examples are illustrativebut not limitative of the present invention and that other embodimentswithin the spirit and scope of the invention will suggest themselves tothose skilled in the art.

We claim:
 1. A 2,7-diazabicyclo [3.3.0]octane of the formula ##STR90##in which R¹, R³, R⁴, R⁵, R⁷ and R⁸ may be identical or different and ineach case denote H, C₁₋ C₅ -alkyl (optionally substituted by halogen,hydroxyl or C₁₋ C₃ -alkoxy), C₁₋ C₃ -alkoxycarbonyl or C₆₋ C₁₂ -aryl,R⁴additionally denotes halogen, R² and R⁶ may be identical or different,denote H, C₁₋ C₆ -alkyl, benzyl, C₆₋ C₁₂ -aryl, C₁₋ C₃ -alkanoyl,benzoyl or C₁₋ C₅ -alkoxycarbonyl, excluding2,7-diazabicyclo[3.3.0]octane.
 2. A compound according to claim 1, inwhichR¹, R³, R⁴, R⁵, R⁷ and R⁸ may be identical or different and denoteH, C₁₋ C₃ -alkyl, C₁₋ C₃ -alkoxycarbonyl or phenyl, R⁴ additionallydenotes fluorine, chlorine or bromine, R² and R⁶ may be identical ordifferent and denote H, C₁₋ C₃ -alkyl, benzyl, C₆₋ C₁₂ -aryl, C₁₋ C₂-alkanoyl, benzoyl or C₁₋ C₄ -alkoxycarbonyl, excluding2,7-diazabicyclo[3.3.0]octane.
 3. A compound according to claim 1, inwhichR¹, R³, R⁴, R⁵, R⁷ and R⁸ may be identical or different and denoteH or methyl, R⁴ additionally denotes chlorine and bromine, R² and R⁶ maybe identical or different and denote H, methyl, phenyl, acetyl or C₂₋ C₄-alkoxycarbonyl, excluding 2,7-diazabicyclo[3.3.0]octane.
 4. A compoundaccording to claim 1, wherein such compound is ethyl2,7-diazabicyclo[3.3.0]octane-2-carboxylate of the formula ##STR91## 5.A compound according to claim 1, wherein such compound is2-methyl-2,7-diazabicyclo[3.3.0]octane of the formula ##STR92##
 6. Acompound according to claim 1, wherein such compound is3-methyl-2,7-diazabicyclo[3.3.0]octane of the formula ##STR93##
 7. Acompound according to claim 1, wherein such compound is7-methyl-2,7-diazabicyclo[3.3.0]octane of the formula ##STR94##
 8. Acompound according to claim 1, wherein such compound is8-methyl-2,7-diazabicyclo[3.3.0]octane of the formula ##STR95##
 9. Acompound according to claim 1, wherein such compound is diethyl2,7-diazabicyclo[3.3.0]octane-3,7-dicarboxylate of the formula ##STR96##